Protein tyrosine kinases are large family of proteins which plays a central role in the regulation of several disorders, particularly in the management of proliferative disorders. Deregulation of tyrosine kinase activity has emerged as a major mechanism by which cancer cells evade normal physiologic constraints on growth, proliferation and survival. An important mechanism leading to tyrosine kinase deregulation is mutation. Chronic myeloid leukaemia (CML) is a chronic myelodysplastic hematopoietic stem cell disorder syndrome. 95% of the CML are resulting from a reciprocal translocation between chromosome-9 and chromosome-22 of Philadelphia chromosome. Break point cluster region (BCR) sequences of chromosome-22 on translocation juxtaposes with the c-ABL tyrosine kinase of chromosome-9. The fusion gene produces a 210 KDa mutant protein in which the first exon of c-ABL has been replaced by BCR sequences, encoding either 927 or 902 amino acid. Another BCR-ABL fusion protein of 185 KDa containing BCR sequences from exon 1 fused to exon 2-11 of c-ABL, is found in 10% of adult ALL patients. The BCR-ABL chimeric gene product has a tyrosine kinase activity several fold higher than its normal counterpart and correlates with the disease phenotype.
Tyrosine kinase forms a significant share of all onco proteins taking a centre stage as possible targets for cancer therapy. The anticancer drug Gleevec/Glivec/Imatinib Mesylate (Novartis STI571) is a block buster drug for the treatment of CML and c-kit positive metastatic GIST. Gleevec selectively and effectively inhibits the kinase activity of BCR-ABL fusion protein, which is responsible for the constitutive proliferative signaling. While Imatinib is therapeutically highly effective, with improving prospects over time for sustained remission and potential to severely limit or eliminate disease progression and transformation, a good number of patients either fail or respond sub optimally to Imatinib. Disease eradication may not be possible with Imatinib.
Distinct patterns of resistance have evolved with the use of Imatinib, and Abl kinase mutations, which alter Imatinib binding or favour kinase conformations inaccessible to Imatinib, Dasatinib and Nilotinib the available alternate Abl kinase inhibitors and restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase. In the advanced disease and Philadelphia chromosome (Ph)+ ALL, responses are more limited and relapse is common.
ABL kinase mutations generally cluster into four main categories and are associated with particular numbered amino acid residues: ATP binding loop (p-loop), particularly Y253 and E255 mutants; T315 mutants; M351 mutants; and activation loop (a-loop), particularly H396 mutants. Modelling of Imatinib and other kinase inhibitors with the crystal structure of the catalytic region of the ABL kinase suggests that mutations may interrupt critical drug contact points or induce or favour a conformation of the Abl kinase in which drug binding is reduced or precluded. Now termed the “gatekeeper” position, mutations at threonine 315 confer resistance both to Imatinib and “second generation” Abl kinase inhibitors Nilotinib and Dasatinib.
Thus there is an unmet need with regard to treatment of patients having the T315I mutation. Omacetaxine (homoharringtonine) is approved by FDA for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). However, it is administered subcutaneously with non-specific mechanism of action. Other drug candidates include rebastinib (WO 2008/046003) and the Ponatinib (WO 2007/075869). Ponatinib (ICLUSIG) is an approved as oral drug candidate and it is developed by Ariad pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib was intended to target not only native BCR-ABL, but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including especially the T315I mutation for which no effective therapy exists. However the Food and Drug Administration temporarily suspended sales of the drug in the U.S. in 2013 because of “the risk of life-threatening blood clots and severe narrowing of blood vessels”. This suspension was partially lifted subsequently with revised prescribing information, a new “Black Box Warning” and a “Risk Evaluation and Mitigation Strategy” in place.
Thus there is a need for newer selective tyrosine kinase inhibitors which are orally active, safer than existing therapies particularly with regard to decrease in risk of life-threatening blood clots and severe narrowing of blood vessels and efficacious against the kinase mutations, including the T315I mutant. The present invention relates to a new family of 1H-1, 8-naphthyridin-2-ones which are potent inhibitors of Abl tyrosine kinase and their mutated forms, including the T315I mutant. The compounds of the present invention are devoid of some of the short comings of the existing drug products.